A Feasibility Study of Year-Long Placebo-Controlled Fluoxetine Treatment in Young Children with Autism

Background: Serotonergic differences have been demonstrated in many individuals with autism, with low levels of synthesis during early childhood when critical neuronal connections are forming.  Fluoxetine increases serotonin levels and was hypothesized to facilitate more typical brain development in children with autism during the highly plastic period between ages two and six years.  However, it was unclear whether a long-term double-blind placebo-controlled developmentally-focused trial was feasible and which outcome measures might be most appropriate.

Objectives: The objectives of the study were to 1) determine enrollment rate; 2) determine the extent of premature withdrawal;  3) evaluate differences in side effects and 4) evaluate the potential sensitivity to change of  various outcome measures.

Methods: Children 30-58 months with autistic disorder confirmed by ADI-R and ADOS were randomly assigned to 12 months of flexible dose treatment with placebo or fluoxetine (1-20mg/day).  Dosing was initiated at 2mg and could be increased by 2mg every 3 weeks.  Dose could be reduced at any time.  Major outcomes were assessed via parent report or by an independent clinician at months 0, 3, 7 and 12.  Outcomes included the Clinical Global Impressions Improvement Score (CGI-IS), PDD Behavior Index (PDD-BI), Preschool Language Scale-4, MacArthur Communication Inventory (MCI), Stanford Binet (IQ), Vineland, Bracken School Readiness, BRIEF-P, RBS-R, Social Reciprocity Scale (SRS), Aberrant Behavior Checklist (ABC), and Caregiver Strain Questionnaire.

Results:

Twenty-nine children were enrolled with nineteen (mean age 42.8 ± 7.3 months) randomized to either fluoxetine (8) or placebo (11) over 18 months across two sites.  The mean duration of treatment was 33 months with 44% completing the entire year of treatment.  Two children in the fluoxetine group and 4 in the placebo group experienced behavioral activation. More children in the fluoxetine group than in the placebo group experienced increased crying (3 vs 0), abdominal discomfort (3 vs 0), rash (5 vs 2), incidental injury (4 vs 0) and other eye disorder (3 vs 0).  One person withdrew early due to adverse effects in the fluoxetine group compared to four people in the placebo group. The CGI-IS, IQ, Bracken, ABC stereotypy and RBS-R did not show any consistent differences between groups.  Several other measures showed consistent numeric differences favoring fluoxetine treatment over time including PDD-BI subscales for autism, specific fears, aggressiveness, social approach, and sematic pragmatic competence, Vineland standard scores, ABC-irritability, lethargy, and hyperactivity subscales and some SRS subscales.  The Caregiver Strain Questionnaire showed consistent, statistically significant benefits of fluoxetine treatment for internalizing and objective stress.

Conclusions: It is feasible to conduct a multisite randomized controlled trial of fluoxetine in young children with autism though recruitment is likely to take about twice as long as other pharmacologic studies in autism.  The Caregiver Strain Questionnaire appears to be sensitive to change with fluoxetine in this heterogeneous population.